U.S. patent application number 12/297282 was filed with the patent office on 2009-11-12 for method of producing polycyclic proline derivative or acid addition salt thereof.
This patent application is currently assigned to Sumitomo Chemical Company, Limited. Invention is credited to Norihiko Hirata, Toshitsugi Uemura, Hideki Ushio.
Application Number | 20090281331 12/297282 |
Document ID | / |
Family ID | 38624672 |
Filed Date | 2009-11-12 |
United States Patent
Application |
20090281331 |
Kind Code |
A1 |
Hirata; Norihiko ; et
al. |
November 12, 2009 |
METHOD OF PRODUCING POLYCYCLIC PROLINE DERIVATIVE OR ACID ADDITION
SALT THEREOF
Abstract
A process for producing proline derivatives of formula (1) below
or acid adduct salts thereof, including: the step of reacting
N-protected pyrrolidinones of formula (2) below with reducing
agents to thereby obtain N-protected pyrrolidinols of formula (3)
below (step A); the step of reacting the N-protected pyrrolidinols
obtained in the step A with cyanating agents to thereby obtain
N-protected cyanopyrrolidines of formula (4) below (step B); the
step of reacting the N-protected cyanopyrrolidines obtained in the
step B with alcohols and bases to thereby obtain imidates of
formula (5) below and treating the imidates with acids to thereby
obtain N-protected prolines of formula (6) below (step C); and the
step of treating the N-protected prolines obtained in the step C
with acids (step D). In formulas (1)-(6) below, any two out of
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are bonded
with each other to thereby form an optionally substituted
C.sub.1-C.sub.4 polymethylene; and R.sup.7 is an optionally
substituted C.sub.1-C.sub.10 linear alkyl, etc. ##STR00001##
Inventors: |
Hirata; Norihiko; (Osaka,
JP) ; Uemura; Toshitsugi; (Osaka, JP) ; Ushio;
Hideki; (Osaka, JP) |
Correspondence
Address: |
PANITCH SCHWARZE BELISARIO & NADEL LLP
ONE COMMERCE SQUARE, 2005 MARKET STREET, SUITE 2200
PHILADELPHIA
PA
19103
US
|
Assignee: |
Sumitomo Chemical Company,
Limited
Chuo-ku, Tokyo
JP
|
Family ID: |
38624672 |
Appl. No.: |
12/297282 |
Filed: |
June 28, 2006 |
PCT Filed: |
June 28, 2006 |
PCT NO: |
PCT/JP2006/313355 |
371 Date: |
October 15, 2008 |
Current U.S.
Class: |
548/452 ;
548/535 |
Current CPC
Class: |
C07D 209/52
20130101 |
Class at
Publication: |
548/452 ;
548/535 |
International
Class: |
C07D 209/00 20060101
C07D209/00; C07D 207/04 20060101 C07D207/04 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 17, 2006 |
JP |
2006-113074 |
Claims
1. A method of producing a proline derivative of the following
formula (1) or an acid addition salt thereof, comprising the
following four steps A to D: ##STR00017## [wherein, any two of
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are
connected to form an optionally substituted polymethylene group
having 1 to 4 carbon atoms, one or no-mutually-adjacent two
methylene groups constituting the polymethylene group may be
substituted by an oxygen atom, one or two ethylene groups
constituting the polymethylene group may be substituted by a
vinylene group, no-mutually adjacent two methylene groups
constituting the polymethylene group may be mutually connected via
an oxygen atom, methylene group, ethylene group or vinylene group,
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 not
constituting the above-described polymethylene group represent each
independently a hydrogen atom, halogen atom, cyano group,
optionally substituted linear, branched or cyclic alkyl group
having 1 to 10 carbon atoms, optionally substituted linear,
branched or cyclic alkenyl group having 2 to 10 carbon atoms,
optionally substituted aryl group having 6 to 20 carbon atoms,
optionally substituted amino group, --OR.sub.a group or --SR.sub.b
group, R.sub.a and R.sub.b represent each independently a hydrogen
atom, alkylcarbonyl group having 2 to 10 carbon atoms, arylcarbonyl
group having 7 to 20 carbon atoms, aralkyl group having 7 to 20
carbon atoms, alkoxyalkyl group having 2 to 10 carbon atoms,
trialkylsilyl group having 3 to 10 carbon atoms, alkyl group having
1 to 10 carbon atoms or aryl group having 6 to 20 carbon atoms,
R.sup.7 represents an optionally substituted linear alkyl group
having 1 to 10 carbon atoms, branched alkyl group having 2 to 10
carbon atoms, linear alkenyl group having 2 to 10 carbon atoms,
branched alkenyl group having 3 to 10 carbon atoms or aralkyl group
having 7 to 20 carbon atoms.] (Step A) A step of reacting
N-protected pyrrolidinones of the following formula (2) with a
reducing agent, to produce N-protected pyrrolidinols of the
following formula (3): ##STR00018## [wherein, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5 and R.sup.6 represent the same meanings
as described above.] ##STR00019## [wherein, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5 and R.sup.6 represent the same meanings
as described above.] (Step B) A step of reacting the N-protected
pyrrolidinols of the formula (3) obtained in the step A with a
cyanodizing agent, to produce N-protected cyanopyrrolidines of the
following formula (4): ##STR00020## [wherein, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5 and R.sup.6 represent the same meanings
as described above.] (Step C) A step of reacting the N-protected
cyanopyrrolidines of the formula (4) obtained in the step B with
alcohols and a base, to obtain imidates of the following formula
(5), and treating the imidates with an acid, to produce N-protected
prolines of the following formula (6): ##STR00021## [wherein,
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7
represent the same meanings as described above.] ##STR00022##
[wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and
R.sup.7 represent the same meanings as described above.] (Step D) A
step of treating the N-protected prolines of the formula (6)
obtained in the step C with an acid, to produce a proline
derivative of the above-described formula (1) or an acid addition
salt thereof.
2. A method of producing a proline derivative of the following
formula (1) or an acid addition salt thereof, comprising the
following three steps A, B and E: ##STR00023## [wherein, R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 represent
the same meanings as described above.] (Step A) A step of reacting
N-protected pyrrolidinones of the following formula (2) with a
reducing agent, to produce N-protected pyrrolidinols of the
following formula (3): ##STR00024## [in the formulae (2) and (3),
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 represent
the same meanings as described above.] (Step B) A step of reacting
the N-protected pyrrolidinols of the formula (3) obtained in the
step A with a cyanodizing agent, to produce N-protected
cyanopyrrolidines of the following formula (4): ##STR00025##
[wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6
represent the same meanings as described above.] (Step E) A step of
reacting the N-protected cyanopyrrolidines of the formula (4)
obtained in the Step B with alcohols and an acid, to produce a
proline derivative of the formula (1) or an acid addition salt
thereof.
3. The production method according to claim 1, wherein R.sup.1 and
R.sup.2 represent a hydrogen atom.
4. The production method according to claim 1, wherein R.sup.3 and
R.sup.5 represent a hydrogen atom.
5. The production method according to claim 1, wherein R.sup.4 and
R.sup.6 are connected to form an optionally substituted
polymethylene group having 1 to 4 carbon atoms.
6. The production method according to claim 1, wherein R.sup.4 and
R.sup.6 are connected to form a (CH.sub.3).sub.2C<group.
7. The production method according to claim 1, wherein R.sup.7 is
an alkyl group having 1 to 4 carbon atoms.
8. The production method according to claim 1, wherein the reducing
agent to be used in the step A is lithium triethylborohydride or
diisobutylaluminum hydride.
9. The production method according to claim 1, wherein the
cyanodizing agent to be used in the step B is trimethylsilyl
cyanide.
10. The production method according to claim 9, wherein the
cyanodizing agent to be used in the step B is trimethylsilyl
cyanide, and a boron trifluoride complex is used together as an
acid catalyst.
11. The production method according to claim 9, wherein N-protected
pyrrolidinols of the formula (3) and trimethylsilyl cyanide are
dropped into a solution containing a boron trifluoride complex.
12. The production method according to claim 1, wherein the acid to
be used in the step D and the step E is hydrogen chloride.
13. The production method according to claim 1, wherein a
post-treatment operation is carried out using an oxidizing agent in
the step B.
14. N-protected pyrrolidinols of the following formula (3):
##STR00026## [wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5
and R.sup.6 represent the same meanings as described above.].
15. The N-protected pyrrolidinols according to claim 14, wherein in
the formula (3), R.sup.1, R.sup.2, R.sup.3 and R.sup.5 represent a
hydrogen atom, and R.sup.4 and R.sup.6 are connected to form an
optionally substituted polymethylene group having 1 to 4 carbon
atoms.
16.
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol.
17.
(1R,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-
-ol.
18. N-protected cyanopyrrolidines of the following formula (4):
##STR00027## [wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5
and R.sup.6 represent the same meanings as described above.].
19. The N-protected cyanopyrrolidines according to claim 18,
wherein in the formula (4), R.sup.1, R.sup.2, R.sup.3 and R.sup.5
represent a hydrogen atom, and R.sup.4 and R.sup.6 are connected to
form an optionally substituted polymethylene group having 1 to 4
carbon atoms.
20.
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbon-
itrile.
21.
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexa-
ne-2-carbonitrile.
22. Imidates of the following formula (5): ##STR00028## (wherein,
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7
represent the same meanings as described above.).
23. The imidates according to claim 22, wherein in the formula (5),
R.sup.1, R.sup.2, R.sup.3 and R.sup.5 represent a hydrogen atom,
R.sup.4 and R.sup.6 are connected to form an optionally substituted
polymethylene group having 1 to 4 carbon atoms and R.sup.7 is an
alkyl group having 1 to 4 carbon atoms.
24.
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboi-
midate.
25. Methyl
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboimida-
te.
26. Methyl
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carboimidate.
Description
TECHNICAL FIELD
[0001] The present invention relates to a method of producing a
polycyclic proline derivative or an acid addition salt thereof.
BACKGROUND ART
[0002] Conventionally, as a method for producing a polycyclic
proline derivative, the following method (see, WO-2004113295) and
the like are known.
##STR00002##
[0003] In the above-described method, however, a multi-stage
complicated process including as many as 9 steps or more is
necessary for production of a final compound I from a raw material
compound II, additionally, the raw material compound II is a meso
form compound, that is, it is necessary to carry out further an
optical-activation treatment in the step I for obtaining the final
compound I as an optically active body, thus, the above-described
method is not recognized as an industrially simple and advantageous
method.
[0004] The present inventors have investigated to find a method of
producing a polycyclic proline derivative having little of the
problems as described above, and found that a polycyclic proline
derivative can be produced simply and industrially advantageously
by using pyrrolidinones as a raw material.
DISCLOSURE OF THE INVENTION
[0005] The present invention has an object of providing a simple
and industrially advantageous method of producing a polycyclic
proline derivative or an acid addition salt thereof.
[0006] That is, the present invention provides the following [1] to
[26].
[0007] [1]. A method of producing a proline derivative of the
following formula (1) or an acid addition salt thereof, comprising
the following four steps A to D:
##STR00003##
[wherein, any two of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5
and R.sup.6 are connected to form an optionally substituted
polymethylene group having 1 to 4 carbon atoms, one or
no-mutually-adjacent two methylene groups constituting the
polymethylene group may be substituted by an oxygen atom, one or
two ethylene groups constituting the polymethylene group may be
substituted by a vinylene group, no-mutually adjacent two methylene
groups constituting the polymethylene group may be mutually
connected via an oxygen atom, methylene group, ethylene group or
vinylene group,
[0008] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 not
constituting the above-described polymethylene group represent each
independently a hydrogen atom, halogen atom, cyano group,
optionally substituted linear, branched or cyclic alkyl group
having 1 to 10 carbon atoms, optionally substituted linear,
branched or cyclic alkenyl group having 2 to 10 carbon atoms,
optionally substituted aryl group having 6 to 20 carbon atoms,
optionally substituted amino group, --OR.sub.a group or --SR.sub.b
group, R.sub.a and R.sub.b represent each independently a hydrogen
atom, alkylcarbonyl group having 2 to 10 carbon atoms, arylcarbonyl
group having 7 to 20 carbon atoms, aralkyl group having 7 to 20
carbon atoms, alkoxyalkyl group having 2 to 10 carbon atoms,
trialkylsilyl group having 3 to 10 carbon atoms, alkyl group having
1 to 10 carbon atoms or aryl group having 6 to 20 carbon atoms,
[0009] R.sup.7 represents an optionally substituted linear alkyl
group having 1 to 10 carbon atoms, branched alkyl group having 2 to
10 carbon atoms, linear alkenyl group having 2 to 10 carbon atoms,
branched alkenyl group having 3 to 10 carbon atoms or aralkyl group
having 7 to 20 carbon atoms.]
(Step A)
[0010] A step of reacting N-protected pyrrolidinones of the
following formula (2) with a reducing agent, to produce N-protected
pyrrolidinols of the following formula (3):
##STR00004##
[wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6
represent the same meanings as described above.]
##STR00005##
[wherein, R.sup.1, R.sup.2R.sup.3R.sup.4, R.sup.5 and R.sup.6
represent the same meanings as described above.]
(Step B)
[0011] A step of reacting the N-protected pyrrolidinols of the
formula (3) obtained in the step A with a cyanodizing agent, to
produce N-protected cyanopyrrolidines of the following formula
(4):
##STR00006##
[wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6
represent the same meanings as described above.]
(Step C)
[0012] A step of reacting the N-protected cyanopyrrolidines of the
formula (4) obtained in the step B with alcohols and a base, to
obtain imidates of the following formula (5), and treating the
imidates with an acid, to produce N-protected prolines of the
following formula (6):
##STR00007##
[wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and
R.sup.7 represent the same meanings as described above.]
##STR00008##
[wherein, R.sup.1, R.sup.2R.sup.3, R.sup.4, R.sup.5, R.sup.6 and
R.sup.7 represent the same meanings as described above.]
(Step D)
[0013] A step of treating the N-protected prolines of the formula
(6) obtained in the step C with an acid, to produce a proline
derivative of the above-described formula (1) or an acid addition
salt thereof.
[0014] [2]. A method of producing a proline derivative of the
following formula (1) or an acid addition salt thereof, comprising
the following three steps A, B and E:
##STR00009##
[wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and
R.sup.7 represent the same meanings as described above.]
(Step A)
[0015] A step of reacting N-protected pyrrolidinones of the
following formula (2) with a reducing agent, to produce N-protected
pyrrolidinols of the following formula (3):
##STR00010##
[in the formulae (2) and (3), R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5 and R.sup.6 represent the same meanings as described
above.]
(Step B)
[0016] A step of reacting the N-protected pyrrolidinols of the
formula (3) obtained in the step A with a cyanodizing agent, to
produce N-protected cyanopyrrolidines of the following formula
(4):
##STR00011##
[wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6
represent the same meanings as described above.]
(Step E)
[0017] A step of reacting the N-protected cyanopyrrolidines of the
formula (4) obtained in the Step B with alcohols and an acid, to
produce a proline derivative of the formula (1) or an acid addition
salt thereof.
[0018] [3]. The production method according to [1] or [2], wherein
R.sup.1 and R.sup.2 represent a hydrogen atom.
[0019] [4]. The production method according to any one of [1] to
[3], wherein R.sup.3 and R.sup.5 represent a hydrogen atom.
[0020] [5]. The production method according to any one of [1] to
[4], wherein R.sup.4 and R.sup.6 are connected to form an
optionally substituted polymethylene group having 1 to 4 carbon
atoms.
[0021] [6]. The production method according to any one of [1] to
[5], wherein R.sup.4 and R.sup.6 are connected to form a
(CH.sub.3).sub.2C<group.
[0022] [7]. The production method according to any one of [1] to
[6], wherein R.sup.7 is an alkyl group having 1 to 4 carbon
atoms.
[0023] [8]. The production method according to any one of [1] to
[7], wherein the reducing agent to be used in the step A is lithium
triethylborohydride or diisobutylaluminum hydride.
[0024] [9]. The production method according to any one of [1] to
[8], wherein the cyanodizing agent to be used in the step B is
trimethylsilyl cyanide.
[0025] [10]. The production method according to [9], wherein the
cyanodizing agent to be used in the step B is trimethylsilyl
cyanide, and a boron trifluoride complex is used together as an
acid catalyst.
[0026] [11]. The production method according to [9] or [10],
wherein N-protected pyrrolidinols of the formula (3) and
trimethylsilyl cyanide are dropped into a solution containing a
boron trifluoride complex.
[0027] [12]. The production method according to any one of [1] to
[11], wherein the acid to be used in the step D and the step E is
hydrogen chloride.
[0028] [13]. The production method according to any one of [1] to
[12], wherein a post-treatment operation is carried out using an
oxidizing agent in the step B.
[0029] [14]. N-protected pyrrolidinols of the following formula
(3):
##STR00012##
[wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6
represent the same meanings as described above.].
[0030] [15]. The N-protected pyrrolidinols according to [14],
wherein in the formula (3), R.sup.1, R.sup.2, R.sup.3 and R.sup.5
represent a hydrogen atom, and R.sup.4 and R.sup.6 are connected to
form an optionally substituted polymethylene group having 1 to 4
carbon atoms.
[0031] [16].
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol.
[0032] [17].
(1R,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol.
[0033] [18]. N-protected cyanopyrrolidines of the following formula
(4):
##STR00013##
[wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6
represent the same meanings as described above.].
[0034] [19]. The N-protected cyanopyrrolidines according to [18],
wherein in the formula (4), R.sup.1, R.sup.2, R.sup.3 and R.sup.5
represent a hydrogen atom, and R.sup.4 and R.sup.6 are connected to
form an optionally substituted polymethylene group having 1 to 4
carbon atoms.
[0035] [20].
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitri-
le.
[0036] [21].
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carbonitrile.
[22]. Imidates of the following formula (5):
##STR00014##
(wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and
R.sup.7 represent the same meanings as described above.).
[0037] [23]. The imidates according to [22], wherein in the formula
(5), R.sup.1, R.sup.2, R.sup.3 and R.sup.5 represent a hydrogen
atom, R.sup.4 and R.sup.6 are connected to form an optionally
substituted polymethylene group having 1 to 4 carbon atoms and
R.sup.7 is an alkyl group having 1 to 4 carbon atoms.
[0038] [24].
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboimida-
te.
[0039] [25]. Methyl
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboimida-
te.
[0040] [26]. Methyl
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carboimidate.
MODES FOR CARRYING OUT THE INVENTION
[0041] The present invention will be illustrated in detail
below.
[0042] The production method of the present invention is a method
containing the four steps A to D described above. First, the step A
of the present invention will be illustrated.
[0043] In the N-protected pyrrolidinones of the formula (2) to be
used in the present invention [hereinafter, abbreviated as
N-protected pyrrolidinones (2) in some cases.], any two of R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are connected to
form an optionally substituted polymethylene group having 1 to 4
carbon atoms, one or no-mutually adjacent two methylene groups
constituting the polymethylene group may be substituted by an
oxygen atom, one or two ethylene groups constituting the
polymethylene group may be substituted by a vinylene group,
no-mutually adjacent two methylene groups constituting the
polymethylene group may be mutually connected via an oxygen atom,
methylene group, ethylene group or vinylene group.
[0044] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 not
constituting the above-described polymethylene group represent each
independently a hydrogen atom, halogen atom, cyano group,
optionally substituted linear, branched or cyclic alkyl group
having 1 to 10 carbon atoms, optionally substituted linear,
branched or cyclic alkenyl group having 2 to 10 carbon atoms,
optionally substituted aryl group having 6 to 20 carbon atoms,
optionally substituted amino group, --OR.sub.a group or --SR.sub.b
group, R.sub.a and R.sub.b represent each independently a hydrogen
atom, alkylcarbonyl group having 2 to 10 carbon atoms, arylcarbonyl
group having 7 to 20 carbon atoms, aralkyl group having 7 to 20
carbon atoms, alkoxyalkyl group having 2 to 10 carbon atoms,
trialkylsilyl group having 3 to 10 carbon atoms, alkyl group having
1 to 10 carbon atoms or aryl group having 6 to 20 carbon atoms.
[0045] Examples of the halogen atom include a chlorine atom,
bromine atom, fluorine atom and iodine atom.
[0046] Examples of the optionally substituted alkyl group having 1
to 10 carbon atoms include alkyl groups having 1 to 10 carbon atoms
such as a methyl group, ethyl group, n-propyl group, isopropyl
group, n-butyl group, cyclohexyl group and the like; halogenated
alkyl groups such as a chloromethyl group, dichloromethyl group,
trichloromethyl group, fluoromethyl group, difluoromethyl group,
trifluoromethyl group and the like; hydroxyalkyl groups such as a
hydroxymethyl group, hydroxyethyl group and the like optionally
substituted by a substituent such as a methyl group, benzyl group,
phenyl group, methoxymethyl group, trimethylsilyl group and the
like; aminoalkyl groups such as an aminomethyl group, aminoethyl
group and the like optionally substituted by a substituent such as
a methyl group, benzyl group, phenyl group, tert-butoxycarbonyl
group, benzyloxycarbonyl group and the like; aralkyl groups such as
a phenylmethyl group, phenylethyl group and the like optionally
substituted by a substituent such as a halogen atom, alkoxy group,
nitro group, cyano group, lower alkyl group, aryl group and the
like; etc.
[0047] Examples of the optionally substituted alkenyl group having
2 to 10 carbon atoms include a vinyl group, ethenyl group,
1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl
group, 3-butenyl group and the like.
[0048] Examples of the optionally substituted aryl group having 6
to 20 carbon atoms include a phenyl group, naphthyl group and the
like optionally substituted by a halogen atom, alkoxy group, nitro
group, cyano group or alkyl group having 1 to 6 carbon atoms.
[0049] Examples of the optionally substituted amino group include
amino groups optionally substituted by a methyl group, benzyl
group, tert-butoxycarbonyl group, benzyloxycarbonyl group and the
like.
[0050] Examples of R.sub.a of the --OR.sub.a group include a
hydrogen atom, alkylcarbonyl groups having 2 to 10 carbon atoms
such as an acetyl group and the like, arylcarbonyl groups having 7
to 20 carbon atoms such as a benzoyl group and the like, aralkyl
groups having 7 to 20 carbon atoms such as a benzyl group and the
like, alkoxyalkyl groups having 2 to 10 carbon atoms such as a
methoxymethyl group and the like, trialkylsilyl groups having 3 to
10 carbon atoms such as a trimethylsilyl group and the like, alkyl
groups having 1 to 10 carbon atoms such as a methyl group, ethyl
group, n-propyl group, isopropyl group, tert-butyl group and the
like, aryl groups having 6 to 20 carbon atoms such as a phenyl
group and the like; etc.
[0051] Examples of R.sub.b of the --SR.sub.b group include a
hydrogen atom, alkylcarbonyl groups having 2 to 10 carbon atoms
such as an acetyl group and the like, arylcarbonyl groups having 7
to 20 carbon atoms such as a benzoyl group and the like, aralkyl
groups having 7 to 20 carbon atoms such as a benzyl group and the
like, alkoxyalkyl groups having 2 to 10 carbon atoms such as a
methoxymethyl group and the like, trialkylsilyl groups having 3 to
10 carbon atoms such as a trimethylsilyl group and the like, alkyl
groups having 1 to 10 carbon atoms such as a methyl group, ethyl
group, n-propyl group, isopropyl group, tert-butyl group and the
like, aryl groups having 6 to 20 carbon atoms such as a phenyl
group and the like; etc.
[0052] As the substituent optionally substituted on a polymethylene
group having 1 to 4 carbon atoms formed by connection of any two of
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 in the
N-protected pyrrolidinones (2), the same substituents as the
above-described substituents represented by R.sup.1, R.sup.2,
R.sup.3R.sup.4, R.sup.5 and R.sup.6 not constituting the
polymethylene group are mentioned.
[0053] Examples of specific structures of the group formed by
connection of any two of R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5 and R.sup.6 include divalent groups of the following
formulae, and the like.
[0054] --CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4--, (CH.sub.3).sub.2C<, (Cl).sub.2C<,
(F).sub.2C<, >CH(CO.sub.2C.sub.2H.sub.5)
##STR00015##
[0055] Examples of the N-protected pyrrolidinones (2) include
3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexan-2-one,
3-tert-butoxycarbonyl-3-azabicyclo[3.2.0]heptan-2-one,
3-tert-butoxycarbonyl-3-azabicyclo[3.3.0]octan-2-one,
8-tert-butoxycarbonyl-8-azabicyclo[4.3.0]nonan-7-one,
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-one,
3-tert-butoxycarbonyl-6,6-dichloro-3-azabicyclo[3.1.0]hexan-2-one,
3-tert-butoxycarbonyl-6,6-difluoro-3-azabicyclo[3.1.0]hexan-2-one,
3-tert-butoxycarbonyl-1-phenyl-3-azabicyclo[3.1.0]hexan-2-one,
4-tert-butoxycarbonyl-4-azatricyclo[5.2.1.0.sup.2,6]deca-3-one,
4-tert-butoxycarbonyl-4-azatricyclo[5.2.2.0.sup.2,6]undeca-3-one,
8-tert-butoxycarbonyl-8-azabicyclo[4.3.0]nonan-3-en-7-one,
4-tert-butoxycarbonyl-4-azatricyclo[5.2.1.0.sup.2,6]deca-8-en-3-one,
4-tert-butoxycarbonyl-4-azatricyclo[5.2.2.0.sup.2,6]undeca-8-en-3-one,
7-tert-butoxycarbonyl-3,3-dimethyl-2,4-dioxa-7-azabicyclo[3.3.0]octan-6-o-
ne,
7-tert-butoxycarbonyl-3-phenyl-2,4-dioxa-7-azabicyclo[3.3.0]octan-6-on-
e,
7-tert-butoxycarbonyl-3,3-dimethyl-2-oxa-7-azabicyclo[3.3.0]octan-6-one-
,
4-tert-butoxycarbonyl-4-aza-10-oxatricyclo[5.2.1.0.sup.2,6]deca-3-one,
4-tert-butoxycarbonyl-4-aza-10-oxatricyclo[5.2.1.0.sup.2,6]deca-8-en-3-on-
e, 2-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexan-3-one,
2-tert-butoxycarbonyl-2-azabicyclo[3.3.0]octan-3-one,
7-tert-butoxycarbonyl-7-azabicyclo[4.3.0]nonan-8-one,
2-tert-butoxycarbonyl-2-azabicyclo[3.3.0]oct-7-en-3-one,
2-tert-butoxycarbonyl-2-azabicyclo[2.2.1]heptan-3-one, and
optically active bodies thereof, and the like.
[0056] The N-protected pyrrolidinones (2) can be produced usually
from the correspondent pyrrolidinones by a general protection
method with N-Boc, for example, by a method using di-tert-butyl
dicarbonate and a base, and the like.
[0057] As the N-protected pyrrolidinones (2), those prepared by
other methods than the above-described methods may also be
used.
[0058] The step A is a step of reacting N-protected pyrrolidinones
(2) with a reducing agent to produce N-protected pyrrolidinols of
the formula (3) [hereinafter, abbreviated as N-protected
pyrrolidinols (3) in some cases.].
[0059] Examples of the above-described reducing agent include
lithium triethylborohydride, diisobutylaluminum hydride, lithium
borohydride, sodium borohydride, tetramethylammonium borohydride,
tetramethylammonium triacetoxy borohydride, lithium aluminum
hydride, tri-tert-butoxylithium aluminum hydride,
tri-sec-butyllithium borohydride, tri-sec-butylpotassium
borohydride, sodium cyano borohydride, sodium
di(2-methoxyethoxy)aluminum hydride, diborane, borane complexes
such as a borane-dimethyl sulfide complex and the like; etc.
[0060] Preferable reducing agents include lithium
triethylborohydride and diisobutylaluminum hydride.
[0061] As these reducing agents, commercially available agents may
be used, and those prepared in the reaction system may be used.
Further, those in the form of solution dissolved in an organic
solvent may be used.
[0062] The use amount of the above-described reducing agent is
usually in the range of 0.3 to 10-mole ratio, preferably 0.5 to
5-mole ratio with respect to N-protected lactams (2).
[0063] The above-described reduction reaction is usually carried
out in the presence of an organic solvent.
[0064] Examples of such an organic solvent include aliphatic
hydrocarbon solvents such as hexane, heptane, cyclohexane and the
like; aromatic solvents such as toluene, xylene, monochlorobenzene,
dichlorobenzene and the like; ether solvents such as
tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane,
1,2-dimethoxyethane and the like; halogenated hydrocarbon solvents
such as dichloromethane, dichloroethane, chlorobutane and the like;
alcohol solvents such as methanol, ethanol, 1-propanol, 2-propanol,
1-butanol, 2-methyl-2-propanol and the like; etc. These solvents
may be used in admixture of two or more.
[0065] The use amount of the organic solvent is usually in the
range of 1 to 100-weight ratio, preferably 2 to 20-weight ratio
with respect to N-protected lactams (2).
[0066] The reduction reaction is usually carried out by a method of
dropping a reducing agent into a solution prepared by dissolving
N-protected pyrrolidinones (2) in an organic solvent, and it may
also be carried out by a method of dropping a solution containing
N-protected pyrrolidinones (2) into a solution containing a
reducing agent.
[0067] The temperature of reduction reaction is usually in the
range of -80 to 30.degree. C., preferably -40 to 10.degree. C.
[0068] By the reduction reaction, a reaction solution containing
N-protected pyrrolidinols (3) is obtained. This reaction solution
is usually subjected to a post-treatment for removal of an
unreacted reducing agent and the like.
[0069] Mentioned as the post-treatment method are, for example, a
method of mixing a reaction solution with water to hydrolyze a
reducing agent, and if necessary, adding an organic solvent
separable from water to cause liquid-partitioning, thereby,
distributing inorganic components obtained by hydrolysis of the
reducing agent into an aqueous layer and distributing N-protected
pyrrolidinols (3) into an organic layer; and other methods.
[0070] In the case of deposition of inorganic components generated
by hydrolysis of a reducing agent, these components may be removed
by a filtration operation.
[0071] The water to be mixed with a reaction solution is not
particularly restricted, and may be neutral water, basic aqueous
solution, or acidic aqueous solution. Preferably used are aqueous
solutions of inorganic bases such as alkali metal hydroxides such
as sodium hydroxide, potassium hydroxide and the like, alkali metal
carbonates such as sodium carbonate, potassium carbonate and the
like, alkali metal bicarbonates such as sodium hydrogen carbonate,
potassium hydrogen carbonate and the like, alkaline earth metal
hydroxides such as magnesium hydroxide, calcium hydroxide and the
like, alkaline earth metal carbonates such as magnesium carbonate,
calcium carbonate and the like.
[0072] As the acid in the case of use of an acidic aqueous
solution, for example, hydrogen chloride, hydrogen bromide,
sulfuric acid, phosphoric acid and the like can be used.
[0073] The use amount of these water, base and acid is not
particularly restricted. An amount necessary for dissolution of
inorganic materials generated by hydrolysis of a reducing agent can
be used, alternatively, an amount just necessary for hydrolysis of
a reducing agent may be used, and inorganic components generated
may be removed by filtration and the like.
[0074] Examples of the organic solvent separable from water
described above include aliphatic hydrocarbon solvents such as
hexane, heptane, cyclohexane and the like; aromatic solvents such
as toluene, xylene, monochlorobenzene, dichlorobenzene and the
like; ether solvents such as methyl tert-butyl ether,
1,2-dimethoxyethane and the like; halogenated hydrocarbon solvents
such as dichloromethane, dichloroethane, chlorobutane and the like;
ketone solvents such as methyl ethyl ketone, methyl isobutyl ketone
and the like; ester solvents such as methyl acetate, ethyl acetate,
butyl acetate and the like; etc.
[0075] The organic layer obtained by liquid-partitioning may be
further subjected to washing with water, washing with basic water,
washing with acidic water, and the like.
[0076] Thus obtained solution containing N-protected pyrrolidinols
(3) may be used as it is in the subsequent step, or may be once
isolated by solvent concentration and the like. Further, it may be
purified by a method such as column chromatography,
re-crystallization or the like.
[0077] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 in
N-protected pyrrolidinols (3) represent the same meanings as for
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 in
N-protected lactams (2).
[0078] Specific examples of N-protected pyrrolidinols (3) include
3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexan-2-ol,
3-tert-butoxycarbonyl-3-azabicyclo[3.2.0]heptan-2-ol,
3-tert-butoxycarbonyl-3-azabicyclo[3.3.0]octan-2-ol,
8-tert-butoxycarbonyl-8-azabicyclo[4.3.0]nonan-7-ol,
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol,
3-tert-butoxycarbonyl-6,6-dichloro-3-azabicyclo[3.1.0]hexan-2-ol,
3-tert-butoxycarbonyl-6,6-difluoro-3-azabicyclo[3.1.0]hexan-2-ol,
3-tert-butoxycarbonyl-1-phenyl-3-azabicyclo[3.1.0]hexan-2-ol,
4-tert-butoxycarbonyl-4-azatricyclo[5.2.1.0.sup.2,6]deca-3-ol,
4-tert-butoxycarbonyl-4-azatricyclo[5.2.2.0.sup.2,6]undeca-3-ol,
8-tert-butoxycarbonyl-8-azabicyclo[4.3.0]nonan-3-ene-7-ol,
4-tert-butoxycarbonyl-4-azatricyclo[5.2.1.0.sup.2,6]deca-8-ene-3-ol,
4-tert-butoxycarbonyl-4-azatricyclo[5.2.2.0.sup.2,6]undeca-8-ene-3-ol,
7-tert-butoxycarbonyl-3,3-dimethyl-2,4-dioxa-7-azabicyclo[3.3.0]octan-6-o-
l,
7-tert-butoxycarbonyl-3-phenyl-2,4-dioxa-7-azabicyclo[3.3.0]octan-6-ol,
7-tert-butoxycarbonyl-3,3-dimethyl-2-oxa-7-azabicyclo[3.3.0]octan-6-ol,
4-tert-butoxycarbonyl-4-aza-10-oxa-tricyclo[5.2.1.0.sup.2,6]deca-3-ol,
4-tert-butoxycarbonyl-4-aza-10-oxa-tricyclo[5.2.1.0.sup.2,6]deca-8-ene-3--
ol, 2-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexan-3-ol,
2-tert-butoxycarbonyl-2-azabicyclo[3.3.0]octan-3-ol,
7-tert-butoxycarbonyl-7-azabicyclo[4.3.0]nonan-8-ol,
2-tert-butoxycarbonyl-2-azabicyclo[3.3.0]octa-7-ene-3-ol,
2-tert-butoxycarbonyl-2-azabicyclo[2.2.1]heptan-3-ol, and optically
active bodies thereof, and the like. When optically active bodies
are used as the N-protected lactams (2), the resultant N-protected
pyrrolidinols (3) are usually optically active bodies.
[0079] Next, the step B of the present invention will be
illustrated.
[0080] The step B is a step of reacting the N-protected
pyrrolidinols (3) obtained in the step A with a cyanodizing agent
in the presence of an acid catalyst, to obtain N-protected
cyanopyrrolidines of the formula (4) [hereinafter, abbreviated as
N-protected cyanopyrrolidines (4) in some cases.].
[0081] Examples of the cyanodizing agent include trimethylsilyl
cyanide, hydrogen cyanide, sodium cyanide, potassium cyanide and
the like. Preferably, trimethylsilyl cyanide is used.
[0082] The use amount of the above-described cyanodizing agent is
usually in the range of 0.8 to 10-mole ratio, preferably 1 to
3-mole ratio with respect to N-protected pyrrolidinols (3).
[0083] Examples of the acid catalyst include boron trifluoride
complexes such as a boron trifluoride-diethyl ether complex, boron
trifluoride-dimethyl sulfide complex and the like, and zinc
chloride, titanium (IV) chloride, tin (IV) chloride, aluminum
chloride, trimethylsilyl trifluoromethanesulfonate, and the like.
As the acid catalyst, boron trifluoride complexes are preferably
used.
[0084] In the case of use of the acid catalyst, the use amount of
the acid catalyst is usually in the range of 0.1 to 5-mole ratio,
preferably 0.5 to 3-mole ratio with respect to N-protected
pyrrolidinols (3).
[0085] The above-described cyanodizing reaction is usually carried
out in an organic solvent. Examples of the organic solvent to be
used in the cyanodizing reaction include aliphatic hydrocarbon
solvents such as hexane, heptane, cyclohexane and the like;
aromatic solvents such as toluene, xylene, monochlorobenzene,
dichlorobenzene, trifluorotoluene and the like; ether solvents such
as tetrahydrofuran, methyl tert-butyl ether, diethyl ether,
1,4-dioxane, 1,2-dimethoxyethane and the like; halogenated
hydrocarbon solvents such as dichloromethane, dichloroethane,
chlorobutane and the like; nitrile solvents such as acetonitrile,
propionitrile and the like; ester solvents such as ethyl acetate,
butyl acetate and the like; etc. These organic solvents may be used
in admixture of two or more.
[0086] The use amount of the organic solvent is usually in the
range of 1 to 100-weight ratio, preferably 2 to 20-weight ratio
with respect to N-protected pyrrolidinols (3).
[0087] As the method for mixing the raw materials and reaction
reagents described above in the cyanodizing reaction, mentioned
are, for example, a method of dropping N-protected pyrrolidinols
(3) and a cyanodizing agent into a solution containing an acid
catalyst, a method of dropping an acid catalyst into a solution
containing N-protected pyrrolidinols (3) and a cyanodizing agent, a
method of dropping N-protected pyrrolidinols (3) into a solution
containing an acid catalyst and a cyanodizing agent, a method of
dropping a cyanodizing agent into a solution containing N-protected
pyrrolidinols (3) and an acid catalyst; and other methods. As the
preferable method in the cyanodizing reaction, a method of dropping
N-protected pyrrolidinols (3) and a cyanodizing agent into a
solution containing an acid catalyst is mentioned.
[0088] The reaction temperature in the above-described cyanodizing
reaction is usually in the range of -100 to 10.degree. C.,
preferably -80 to -10.degree. C.
[0089] After completion of such a cyanodizing reaction, a solution
containing N-protected cyanopyrrolidines (4) is obtained, and after
completion of the reaction, a post-treatment operation is usually
carried out for removal of an excess amount of cyanodizing agent
and acid catalyst in the reaction liquid.
[0090] In the post-treatment operation, for example, a reaction
solution and water are mixed, then, if necessary, an organic
solvent separable from water is added to cause liquid-partitioning,
thus, an excess amount of cyanodizing agent and acid catalyst, and
inorganic components obtained by hydrolysis thereof, can be
distributed in an aqueous layer. Meanwhile, the aimed compound,
N-protected cyanopyrrolidines (4) can be distributed into an
organic layer. Further, when pH in the post treatment is alkaline,
a cyanodizing agent, acid catalyst and inorganic components
obtained by hydrolysis thereof can be distributed efficiently into
an aqueous layer, thus, it is preferable that, in the
above-described post treatment, the reaction solution and water are
mixed, then, a base is added to make it alkaline, or a basic
aqueous solution is used as the water to be mixed with the reaction
solution. The range of pH in the post-treatment operation is
usually from 7 to 14, preferably 9 to 13.
[0091] As the base to be used in the post-treatment operation,
inorganic bases such as alkali metal hydroxides such as sodium
hydroxide, potassium hydroxide and the like, alkali metal
carbonates such as sodium carbonate, potassium carbonate and the
like, alkali metal bicarbonates such as sodium hydrogen carbonate,
potassium hydrogen carbonate and the like; etc are used.
[0092] Examples of the above-described organic solvent separable
from water include aliphatic hydrocarbon solvents such as hexane,
heptane, cyclohexane and the like; aromatic solvents such as
toluene, xylene, monochlorobenzene, dichlorobenzene and the like;
ether solvents such as methyl tert-butyl ether, 1,2-dimethoxyethane
and the like; halogenated hydrocarbon solvents such as
dichloromethane, dichloroethane, chlorobutane and the like; ketone
solvents such as methyl ethyl ketone, methyl isobutyl ketone and
the like; ester solvents such as methyl acetate, ethyl acetate,
butyl acetate and the like; etc.
[0093] The resultant organic layer may further be subjected to
washing with water, washing with basic water, washing with acidic
water, and the like.
[0094] For decomposing a toxic cyanodizing agent, it is preferable
to carry out a post-treatment operation using an oxidizing agent.
As the oxidizing agent, for example, sodium hypochlorite, hydrogen
peroxide and the like are used. The treatment with an oxidizing
agent is preferably carried out under a basic condition. In this
case, the range of pH is usually from 7 to 14, preferably 9 to 13.
In the above-described post treatment using a basic aqueous
solution, an oxidizing agent may be added in performing the
treatment.
[0095] After the above-described treatment using an oxidizing
agent, neutralization may further be carried out using an acid, and
additionally, a treatment with a reducing agent may be carried out
for the purpose of decomposing an excess amount of oxidizing agent.
Examples of the acid include aqueous solutions of inorganic acids
such as hydrochloric acid, hydrobromic acid, sulfuric acid,
phosphoric acid and the like, aqueous solutions of organic acids
such as acetic acid, citric acid and the like; etc. Examples of the
reducing agent include aqueous solutions of sodium sulfite, sodium
thiosulfate and the like.
[0096] Thus obtained solution containing N-protected
cyanopyrrolidines (4) may be used as it is in the subsequent step,
or may be once isolated by solvent concentration and the like.
Further, it may be purified by a method such as column
chromatography, re-crystallization or the like.
[0097] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 in
N-protected cyanopyrrolidines (4) represent the same meanings as
for R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 defined
in N-protected pyrrolidinones (2).
[0098] Examples of the N-protected cyanopyrrolidines (4) include
3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexane-2-carbonitrile,
3-tert-butoxycarbonyl-3-azabicyclo[3.2.0]heptane-2-carbonitrile,
3-tert-butoxycarbonyl-3-azabicyclo[3.3.0]octan-2-carbonitrile,
8-tert-butoxycarbonyl-8-azabicyclo[4.3.0]nonan-7-carbonitrile,
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitri-
le,
3-tert-butoxycarbonyl-6,6-dichloro-3-azabicyclo[3.1.0]hexane-2-carboni-
trile,
3-tert-butoxycarbonyl-6,6-difluoro-3-azabicyclo[3.1.0]hexane-2-carb-
onitrile,
3-tert-butoxycarbonyl-1-phenyl-3-azabicyclo[3.1.0]hexane-2-carbo-
nitrile,
4-tert-butoxycarbonyl-4-azatricyclo[5.2.1.0.sup.2,6]deca-3-carbon-
itrile,
4-tert-butoxycarbonyl-4-azatricyclo[5.2.2.0.sup.2,6]undeca-3-carbo-
nitrile,
8-tert-butoxycarbonyl-8-azabicyclo[4.3.0]nonan-3-ene-7-carbonitri-
le,
4-tert-butoxycarbonyl-4-azatricyclo[5.2.1.0.sup.2,6]deca-8-ene-3-carbo-
nitrile,
4-tert-butoxycarbonyl-4-azatricyclo[5.2.2.0.sup.2,6]undeca-8-ene--
3-carbonitrile,
7-tert-butoxycarbonyl-3,3-dimethyl-2,4-dioxa-7-azabicyclo[3.3.0]octan-6-c-
arbonitrile,
7-tert-butoxycarbonyl-3-phenyl-2,4-dioxa-7-azabicyclo[3.3.0]octan-6-carbo-
nitrile,
7-tert-butoxycarbonyl-3,3-dimethyl-2-oxa-7-azabicyclo[3.3.0]octan-
-6-carbonitrile,
4-tert-butoxycarbonyl-4-aza-10-oxa-tricyclo[5.2.1.0.sup.2,6]deca-3-carbon-
itrile,
4-tert-butoxycarbonyl-4-aza-10-oxa-tricyclo[5.2.1.0.sup.2,6]deca-8-
-ene-3-carbonitrile,
2-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carbonitrile,
2-tert-butoxycarbonyl-2-azabicyclo[3.3.0]octan-3-carbonitrile,
7-tert-butoxycarbonyl-7-azabicyclo[4.3.0]nonan-8-carbonitrile,
2-tert-butoxycarbonyl-2-azabicyclo[3.3.0]octa-7-ene-3-carbonitrile,
2-tert-butoxycarbonyl-2-azabicyclo[2.2.1]heptane-3-carbonitrile and
the like.
[0099] As the N-protected cyanopyrrolidines (4), optically active
bodies of the above-exemplified compounds, and the like are
mentioned. When optically active bodies are used as the N-protected
pyrrolidinols (3), the resultant N-protected cyanopyrrolidines (4)
are usually optically active bodies.
[0100] Next, the step C of the present invention will be
illustrated.
[0101] The step C is a step of reacting the N-protected
cyanopyrrolidines (4) obtained in the step B with alcohols in the
presence of a base, to obtain imidates of the formula (5)
[hereinafter, abbreviated as imidates (5) in some cases.] as an
intermediate, then, treating with an acid to obtain N-protected
prolines of the formula (6) [hereinafter, abbreviated as
N-protected prolines (6) in some cases.].
[0102] Examples of the alcohols include alkyl alcohols having 1 to
10 carbon atoms, alkenyl alcohols having 2 to 10 carbon atoms,
aralkyl alcohols having 7 to 20 carbon atoms and the like such as
methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol,
2-methyl-1-propanol, 2-methyl-2-propanol, allyl alcohol, benzyl
alcohol, p-methoxybenzyl alcohol, and the like.
[0103] The above-described alcohols can be used also as a reaction
solvent. The use amount of the above-described alcohols is usually
in the range of 0.2 to 50-weight ratio, preferably 2 to 20-weight
ratio with respect to N-protected cyanopyrrolidines (4).
[0104] Examples of other reaction solvents than the above-described
alcohols include aliphatic hydrocarbon solvents such as hexane,
heptane, cyclohexane and the like; aromatic solvents such as
toluene, xylene, monochlorobenzene, dichlorobenzene and the like;
ether solvents such as tetrahydrofuran, methyl tert-butyl ether,
1,4-dioxane, 1,2-dimethoxyethane and the like; halogenated
hydrocarbon solvents such as dichloromethane, dichloroethane,
chlorobutane and the like; ketone solvents such as acetone, methyl
ethyl ketone, methyl isobutyl ketone and the like; ester solvents
such as methyl acetate, ethyl acetate, butyl acetate and the like;
amide solvents such as N,N-dimethylformamide,
N,N-dimethylacetamide, N-methylpyrrolidinone and the like; etc.
These solvents may be used singly or in admixture of two or
more.
[0105] Examples of the base include alkali metal hydroxides such as
sodium hydroxide, potassium hydroxide and the like; alkali metal
carbonate addition salts such as sodium carbonate, potassium
carbonate, cesium carbonate and the like; alkali metal alcoholates
such as sodium methoxide, sodium ethoxide and the like; alkali
metal hydrides such as sodium hydride, potassium hydride and the
like; organic bases such as triethylamine, diisopropylethylamine,
1,8-diazabicyclo[5.4.0]undeca-7-ene, pyridine and the like;
etc.
[0106] The use amount of the above-described base is usually in the
range of 0.5 to 10-mole ratio, preferably 1 to 5-mole ratio with
respect to N-protected cyanopyrrolidines (4).
[0107] The reaction temperature in obtaining imidates (5) from
N-protected cyanopyrrolidines (4) is usually in the range of -30 to
30.degree. C., preferably -20 to 10.degree. C.
[0108] A solution containing imidates (5) obtained in the
above-described reaction can be derived into N-protected prolines
(6) by an acid treatment such as mixing with acidic water, or the
like.
[0109] The treatment with acidic water includes, for example, a
method of adding acidic water into a reaction solution containing
imidates (5), a method of adding the above-described reaction
solution into acidic water, a method of mixing the above-described
reaction solution and water, then, adding acidic water, and other
methods.
[0110] In the above-described reaction, the reaction temperature is
usually in the range of -20 to 20.degree. C., preferably -10 to
10.degree. C., so as to prevent side reactions such as
decomposition of imidates (5), hydrolysis of an ester group in
N-protected prolines (6), de-protection of an N-protective group in
N-protected prolines (6), and the like. For suppressing the
above-described side reactions and decomposition reactions, the
above-described reaction solution and acidic water may be poured
simultaneously so as to keep pH in dropping neutral.
[0111] Examples of the above-described acidic water include aqueous
solutions of inorganic acids such as hydrochloric acid, hydrobromic
acid, sulfuric acid, phosphoric acid and the like, aqueous
solutions of organic acids such as acetic acid, citric acid and the
like; etc.
[0112] The use amount of these acids is usually in the range of 1
to 20-mole ratio with respect to N-protected cyanopyrrolidines (4),
and preferably is an amount obtained by adding 0.5 to 2-mole ratio
with respect to N-protected cyanopyrrolidines (4) to the amount of
an acid required for neutralizing a base used in the reaction of
obtaining imidates (5).
[0113] If necessary, an organic solvent separable from water can be
added to the N-protected prolines (6) in the reaction solution,
thereby, distributing the N-protected prolines (6) into an organic
layer.
[0114] Examples of the organic solvent separable from water to be
used in distribution include aliphatic hydrocarbon solvents such as
hexane, heptane, cyclohexane and the like; aromatic solvents such
as toluene, xylene, monochlorobenzene, dichlorobenzene and the
like; ether solvents such as methyl tert-butyl ether,
1,2-dimethoxyethane and the like; halogenated hydrocarbon solvents
such as dichloromethane, dichloroethane, chlorobutane and the like;
ketone solvents such as methyl ethyl ketone, methyl isobutyl ketone
and the like; ester solvents such as methyl acetate, ethyl acetate,
butyl acetate and the like; etc.
[0115] The use amount of the organic solvent is usually in the
range of 1 to 100-weight ratio, preferably 2 to 20-weight ratio
with respect to N-protected cyanopyrrolidines (4).
[0116] The resultant organic layer may further be subjected to
washing with water, washing with basic water, washing with acidic
water, and the like.
[0117] Thus obtained solution containing N-protected prolines (6)
may be used as it is in the subsequent step, or may be once
isolated by solvent concentration and the like. It may be further
purified by a method such as column chromatography,
re-crystallization or the like.
[0118] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 in
N-protected prolines (6) represent the same meanings as for
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 defined in
N-protected pyrrolidinones (2).
[0119] R.sup.7 represents an optionally substituted alkyl group
having 1 to 10 carbon atoms, optionally substituted alkenyl group
having 2 to 10 carbon atoms or optionally substituted aralkyl group
having 7 to 20 carbon atoms.
[0120] Specific examples of N-protected prolines (6) include
compounds such as
3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid
methyl ester,
3-tert-butoxycarbonyl-3-azabicyclo[3.2.0]heptane-2-carboxylic acid
methyl ester,
3-tert-butoxycarbonyl-3-azabicyclo[3.3.0]octane-2-carboxylic acid
methyl ester,
8-tert-butoxycarbonyl-8-azabicyclo[4.3.0]nonane-7-carboxylic acid
methyl ester,
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-car-
boxylic acid methyl ester,
3-tert-butoxycarbonyl-6,6-dichloro-3-azabicyclo[3.1.0]hexane-2-carboxylic
acid methyl ester,
3-tert-butoxycarbonyl-6,6-difluoro-3-azabicyclo[3.1.0]hexane-2-carboxylic
acid methyl ester,
3-tert-butoxycarbonyl-1-phenyl-3-azabicyclo[3.1.0]hexane-2-carboxylic
acid methyl ester,
4-tert-butoxycarbonyl-4-azatricyclo[5.2.1.0.sup.2,6]deca-3-carboxylic
acid methyl ester,
4-tert-butoxycarbonyl-4-azatricyclo[5.2.2.0.sup.2,6]undeca-3-carboxylic
acid methyl ester,
8-tert-butoxycarbonyl-8-azabicyclo[4.3.0]nonan-3-ene-7-carboxylic
acid methyl ester,
4-tert-butoxycarbonyl-4-azatricyclo[5.2.1.0.sup.2,6]deca-8-ene-3-carboxyl-
ic acid methyl ester,
4-tert-butoxycarbonyl-4-azatricyclo[5.2.2.0.sup.2,6]undeca-8-ene-3-carbox-
ylic acid methyl ester,
7-tert-butoxycarbonyl-3,3-dimethyl-2,4-dioxa-7-azabicyclo[3.3.0]octan-6-c-
arboxylic acid methyl ester,
7-tert-butoxycarbonyl-3-phenyl-2,4-dioxa-7-azabicyclo[3.3.0]octan-6-carbo-
xylic acid methyl ester,
7-tert-butoxycarbonyl-3,3-dimethyl-2-oxa-7-azabicyclo[3.3.0]octan-6-carbo-
xylic acid methyl ester,
4-tert-butoxycarbonyl-4-aza-10-oxa-tricyclo[5.2.1.0.sup.2,6]deca-3-carbox-
ylic acid methyl ester,
4-tert-butoxycarbonyl-4-aza-10-oxa-tricyclo[5.2.1.0.sup.2,6]deca-8-ene-3--
carboxylic acid methyl ester,
2-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid
methyl ester,
2-tert-butoxycarbonyl-2-azabicyclo[3.3.0]octan-3-carboxylic acid
methyl ester,
7-tert-butoxycarbonyl-7-azabicyclo[4.3.0]nonan-8-carboxylic acid
methyl ester,
2-tert-butoxycarbonyl-2-azabicyclo[3.3.0]octa-7-ene-3-carboxylic
acid methyl ester,
2-tert-butoxycarbonyl-2-azabicyclo[2.2.1]heptane-3-carboxylic acid
methyl ester, and the like.
[0121] Also mentioned are compounds obtained by substitution of a
methyl ester group in these compounds with an ethyl ester group,
n-propyl ester group, isopropyl ester group, n-butyl ester group,
sec-butyl ester group, isobutyl ester group, tert-butyl ester
group, allyl ester group, benzyl ester group, p-methoxybenzyl ester
group, and the like.
[0122] Further, optically active bodies of the above-described
compounds are also mentioned. When optically active bodies are used
as the N-protected cyanopyrrolidines (4), the resultant N-protected
prolines (6) are usually optically active bodies.
[0123] Next, the step D of the present invention will be
illustrated.
[0124] The step D is a step of treating the N-protected prolines
(6) obtained in the step C with an acid to de-protect an
N-protective group in the N-protected prolines (6), thereby
obtaining a proline derivative of the formula (1) [hereinafter,
abbreviated as proline derivative (1) in some cases.].
[0125] Examples of the de-protection reaction method include a
method of dropping an acid or a solution containing an acid into a
solution prepared by dissolving N-protected prolines (6) in a
solvent, a method of blowing an acid in the form of gas into a
solution prepared by dissolving N-protected prolines (6) in a
solvent, a method of dropping a solution containing N-protected
prolines (6) into an acid or a solution containing an acid, and
other methods.
[0126] Examples of the above-described acid include inorganic acids
such as hydrogen chloride, hydrogen bromide, sulfuric acid and the
like, and organic acids such as methanesulfonic acid,
trifluoroacetic acid and the like.
[0127] The use amount of the above-described acid is usually in the
range of 0.5 to 20-mole ratio, preferably 1 to 10-mole ratio with
respect to N-protected prolines (6).
[0128] The de-protection reaction is usually carried out in a
solvent. Example of the above-described solvent include alcohol
solvents such as methanol, ethanol, 1-propanol, 2-propanol,
1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol and
the like; aliphatic hydrocarbon solvents such as hexane, heptane,
cyclohexane and the like; aromatic solvents such as toluene,
xylene, monochlorobenzene, dichlorobenzene and the like; ether
solvents such as tetrahydrofuran, methyl tert-butyl ether,
1,4-dioxane, 1,2-dimethoxyethane and the like; halogenated
hydrocarbon solvents such as dichloromethane, dichloroethane,
chlorobutane and the like; ester solvents such as methyl acetate,
ethyl acetate, butyl acetate and the like; and water, and the like.
These solvents may be used singly or in admixture of two or
more.
[0129] When alcohol solvents and ester solvents are used, it is
preferable to use an alcohol solvent or ester solvent corresponding
to an ester group R.sup.7 in N-protected prolines (6), so as not to
cause a transesterification reaction with the ester group in
N-protected prolines (6).
[0130] For example, in the case of production of a compound in
which R.sup.7 in N-protected prolines (6) is a methyl group, it is
preferable to use methanol as the corresponding alcohol solvent. In
the case of production of a compound in which R.sup.7 is an ethyl
group, it is preferable to use ethyl acetate as the corresponding
ester solvent.
[0131] The use amount of the above-described organic solvent is
usually in the range of 0.5 to 100-weight ratio, preferably 1 to
20-weight ratio with respect to N-protected prolines (6).
[0132] The reaction temperature in the de-protection reaction is
usually in the range of -20 to 100.degree. C., preferably 0 to
50.degree. C.
[0133] Thus, a proline derivative (1) is obtained, and after
completion of the above-described de-protection reaction, the
proline derivative (1) is usually present as an addition salt of an
acid used in the reaction, and by concentrating the reaction
solution to dryness, an acid addition salt of the proline
derivative (1) can be taken out.
[0134] When the acid addition salt of the proline derivative (1)
deposits as solid after completion of the reaction, the aimed acid
addition salt of the proline derivative (1) can be isolated by
filtration and the like. Further, when the deposition amount of the
acid addition salt of the proline derivative (1) is small, its
deposition amount can be increased by adding a poor solvent for the
acid addition salt of the proline derivative (1). Also in the case
of no deposition of the acid addition salt of the proline
derivative (1), the acid addition salt of the proline derivative
(1) can be crystallized and taken out as solid by adding a poor
solvent.
[0135] By cooling the reaction solution after completion of the
de-protection reaction, the acid addition salt of the proline
derivative (1) may be crystallized, and the deposition amount of
the acid addition salt of the proline derivative (1) can be
increased.
[0136] Examples of the above-described poor solvent include organic
solvents such as aliphatic hydrocarbon solvents such as hexane,
heptane, cyclohexane and the like; aromatic solvents such as
toluene, xylene, monochlorobenzene, dichlorobenzene and the like;
ether solvents such as tetrahydrofuran, methyl tert-butyl ether,
1,4-dioxane, 1,2-dimethoxyethane and the like; halogenated
hydrocarbon solvents such as dichloromethane, dichloroethane,
chlorobutane and the like; ester solvents such as methyl acetate,
ethyl acetate, butyl acetate and the like; etc. These organic
solvents may be used singly or in admixture of two or more.
[0137] The use amount of the above-described organic solvent is
usually in the range of 0 to 200-weight ratio, preferably 1 to
50-weight ratio with respect to N-protected prolines (6).
[0138] The resultant acid addition salt of the proline derivative
(1) may be further purified by a method such as re-crystallization
and the like.
[0139] For example, by mixing solid of the acid addition salt of
the proline derivative (1) obtained in the above-described
operation with water and an organic solvent separable from water,
and neutralizing an acid forming the addition salt using a base, a
free proline derivative (1) can be extracted into the organic
solvent. Further, also by adding a base for neutralizing the acid
used and water, and if necessary, an organic solvent separable from
water, to the reaction solution obtained after the de-protection
reaction, and performing extraction, a free proline derivative (1)
can be obtained in the organic solvent.
[0140] The extraction operation with the organic solvent may be
repeated. Extraction efficiency can also be enhanced by adding an
inorganic salt and the like.
[0141] Examples of the organic solvent separable from water include
aliphatic hydrocarbon solvents such as hexane, heptane, cyclohexane
and the like; aromatic solvents such as toluene, xylene,
monochlorobenzene, dichlorobenzene and the like; ether solvents
such as methyl tert-butyl ether, 1,2-dimethoxyethane and the like;
halogenated hydrocarbon solvents such as dichloromethane,
dichloroethane, chlorobutane and the like; ketone solvents such as
methyl ethyl ketone, methyl isobutyl ketone and the like; ester
solvents such as methyl acetate, ethyl acetate, butyl acetate and
the like; etc.
[0142] Examples of the base include inorganic bases such as alkali
metal hydroxides such as sodium hydroxide, potassium hydroxide and
the like; alkali metal carbonates such as sodium carbonate,
potassium carbonate and the like; alkali metal bicarbonates such as
sodium hydrogen carbonate, potassium hydrogen carbonate and the
like; alkali metal phosphates such as trisodium phosphate,
tripotassium phosphate, disodium hydrogen phosphate, dipotassium
hydrogen phosphate and the like; organic bases such triethylamine,
pyridine, piperidine and the like; and ammonia and the like.
[0143] The inorganic salt to be added for enhancing the extraction
efficiency is not particularly restricted, and for example, sodium
chloride, potassium chloride, ammonium chloride, sodium hydrogen
carbonate, potassium hydrogen carbonate and the like are
mentioned.
[0144] The resultant organic layer contains a free proline
derivative (1), and the aimed free proline derivative (1) can be
isolated by a method such as concentration of the organic solvent,
and the like. The free proline derivative (1) gives rise to a
dehydration reaction, thereby forming for example a dimer such as
diketopiperazine and the like in some cases, thus, the
concentration of the organic solvent is preferably carried out at a
temperature which is as low as possible, usually about -10.degree.
C. to 40.degree. C. The free proline derivative (1) obtained by
concentration of the organic solvent and the like may be purified
by a method such as column chromatography, re-crystallization and
the like.
[0145] The production method of the present invention is also a
method containing three steps: the step A and step B described
above, and a step E described later.
[0146] The step E of the present invention will be illustrated.
[0147] The step E is a step of reacting N-protected
cyanopyrrolidines of the formula (4) obtained via the step A and
the step B with alcohols and an acid, to produce a proline
derivative of the formula (1) or acid addition salt thereof.
[0148] The step E can be carried out in the same manner as in the
step D excepting that N-protected cyanopyrrolidines (4) are used
instead of N-protected prolines (6) as a raw material compound in
the step D. As the alcohols and acid to be used, the same compounds
as described above are mentioned.
[0149] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 in
the proline derivative (1) represent the same meanings as for
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 defined in
the N-protected pyrrolidinones (2).
[0150] R.sup.7 represents the same meaning as for R.sup.7 defined
in the N-protected prolines (6).
[0151] Examples of the proline derivative (1) include
3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester,
3-azabicyclo[3.2.0]heptane-2-carboxylic acid methyl ester,
3-azabicyclo[3.3.0]octane-2-carboxylic acid methyl ester,
8-azabicyclo[4.3.0]nonane-7-carboxylic acid methyl ester,
6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl
ester, 6,6-dichloro-3-azabicyclo[3.1.0]hexane-2-carboxylic acid
methyl ester, 6,6-difluoro-3-azabicyclo[3.1.0]hexane-2-carboxylic
acid methyl ester, 1-phenyl-3-azabicyclo[3.1.0]hexane-2-carboxylic
acid methyl ester, 4-azatricyclo[5.2.1.0.sup.2,6]deca-3-carboxylic
acid methyl ester,
4-azatricyclo[5.2.2.0.sup.2,6]undeca-3-carboxylic acid methyl
ester, 8-azabicyclo[4.3.0]nonan-3-ene-7-carboxylic acid methyl
ester, 4-azatricyclo[5.2.1.0.sup.2,6]deca-8-ene-3-carboxylic acid
methyl ester,
4-azatricyclo[5.2.2.0.sup.2,6]undeca-8-ene-3-carboxylic acid methyl
ester, 3,3-dimethyl-2,4-dioxa-7-azabicyclo[3.3.0]octan-6-carboxylic
acid methyl ester,
3-phenyl-2,4-dioxa-7-azabicyclo[3.3.0]octan-6-carboxylic acid
methyl ester,
3,3-dimethyl-2-oxa-7-azabicyclo[3.3.0]octan-6-carboxylic acid
methyl ester,
4-aza-10-oxa-tricyclo[5.2.1.0.sup.2,6]deca-3-carboxylic acid methyl
ester,
4-aza-10-oxa-tricyclo[5.2.1.0.sup.2,6]deca-8-ene-3-carboxylic acid
methyl ester, 2-azabicyclo[3,1,0]hexane-3-carboxylic acid methyl
ester, 2-azabicyclo[3.3.0]octan-3-carboxylic acid methyl ester,
7-azabicyclo[4.3.0]nonan-8-carboxylic acid methyl ester,
2-azabicyclo[3.3.0]octa-7-ene-3-carboxylic acid methyl ester,
2-azabicyclo[2.2.1]heptane-3-carboxylic acid methyl ester, and the
like.
[0152] Further, compounds obtained by substituting the
above-described methyl ester by an ethyl ester, n-propyl ester,
isopropyl ester, n-butyl ester, sec-butyl ester, isobutyl ester,
tert-butyl ester, allyl ester, benzyl ester or p-methoxybenzyl
ester, and the like, are mentioned.
[0153] Furthermore, acid addition salts obtained by addition of an
inorganic acid such as hydrogen chloride, hydrogen bromide,
sulfuric acid and the like, and acid addition salts obtained by
addition of an organic acid such as methanesulfonic acid,
trifluoroacetic acid and the like, to the above-described proline
derivative (1), are also exemplified.
[0154] Still further, optically active bodies of the
above-described proline derivatives (1) or acid addition salts
thereof are also mentioned. When optically active bodies are used
as the N-protected prolines (6), the resultant proline derivatives
(1) or acid addition salts thereof are usually optically active
bodies.
[0155] According to the present invention, a proline derivative (1)
or acid addition salt thereof can be produced simply and
industrially advantageously from the correspondent
pyrrolidinones.
[0156] The proline derivative (1) or acid addition salt thereof
obtained in the present invention is useful as a chemical raw
material or medical-agricultural drug intermediate, and for
example, can be used suitably as a production intermediate for the
following compound (see, WO 2004/113295) as one of anti-hepatitis C
drugs (HCV drug).
##STR00016##
EXAMPLES
[0157] The present invention will be illustrated further in detail
based on examples below, but it is needless to say that the present
invention is not limited to these examples.
Example 1
Synthesis Example of
(1R,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol
[0158] 25.0 g (111 mmol) of
(1R,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-one
and 25 g of tetrahydrofuran were mixed, and cooled down to
-10.degree. C., then, 105 g of a toluene solution (1 mol/l) of
diisobutylaluminum hydride was dropped at -10.degree. C. over a
period of 3 hours. After completion of dropping, the mixture was
stirred for 1 hour at the same temperature, then, the reaction
liquid was heated up to 20.degree. C. After rising of temperature,
22 g of a 2% sodium hydroxide aqueous solution was dropped, then,
the mixture was stirred at 25.degree. C. The deposited crystal was
filtrated, thereby obtaining a filtrate.
[0159] Next, the resultant materials on the filter were washed with
80 g of tetrahydrofuran, obtaining washing liquid.
[0160] The above-described filtrate and washing liquid were mixed
to obtain a solution which was then washed three times with 22 g of
a 2% sodium hydroxide aqueous solution. This washing includes
mixing under stirring and liquid-partitioning under still
standing.
[0161] The resultant organic layer was washed twice with 22 g of
15% saline. The organic layer obtained after washing was
concentrated under reduced pressure condition, then, to the
resultant concentration residue was added 75 g of toluene and 25 g
of water and mixed before liquid-partitioning.
[0162] The resultant organic layer was concentrated under reduced
pressure to distill off the solvent, obtaining 25.0 g of a solution
containing 24.1 g (106 mmol) of
(1R,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol.
[0163] The yield with respect to
(1R,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-one
was 95.5%.
[0164] The quantitative determination of
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol
was performed by high performance liquid chromatography. As the
column, ZORBAX SB-Phenyl, 4.6 mm .phi..times.250 mm, 5 .mu.m,
manufactured by Agilent was used.
[0165] The measurement results of .sup.1H-NMR (DMSO-d6) of
(1R,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol
are shown below.
[0166] .delta.=5.22 to 4.99 m (1H), 3.43 dd (1H), 3.24 dd (1H),
1.38 s (9H), 1.47 to 1.13 m (2H), 0.96 s (3H), 0.82 s (3H).
Example 2
Synthesis Example of
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol
[0167] 11.0 g (49 mmol) of
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-one
and 196 g of tetrahydrofuran were mixed, and cooled down to
-20.degree. C., then, 59 ml of a tetrahydrofuran solution (1 mol/l)
of lithium triethylborohydride was dropped at -20.degree. C. After
completion of dropping, the mixture was stirred for 2 hours at the
same temperature, then, 142 g of a 7% sodium hydrogen carbonate
aqueous solution was added, and heated up to 0.degree. C. After
rising of temperature, 13 g of 30% hydrogen peroxide water was
dropped. After stirring at 0.degree. C. for 30 minutes, the solvent
was distilled off by concentration under reduced pressure. To the
residue obtained after solvent distilling off was added 100 ml of
water and 100 ml of methyl tert-butyl ether and mixed before liquid
partitioning. Further, the aqueous layer obtained after
liquid-partitioning was subjected to an extraction and
liquid-partitioning operation twice using 100 ml of methyl
tert-butyl ether. The resultant organic layers were combined to
give a solution to which sodium sulfate was added, and mixed, then,
solid was removed by filtration, and the filtrate was concentrated
under reduced pressure to distill off the solvent, obtaining 11.0 g
of 3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol
in the form of white solid. The yield of
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol
with respect to
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-one
was 98.5%.
[0168] The measurement results by .sup.1H-NMR (DMSO-d6) of
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol
are shown below.
[0169] .delta.=5.48 to 5.45 m (1H), 3.42 dd (1H), 3.24 d (1H), 1.49
to 1.44 m (1H), 1.40 s (9H), 1.31 to 1.26 m (1H), 1.17 (3H), 0.98 s
(3H).
Example 3
Synthesis Example of
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol
[0170] 0.50 g (2.2 mmol) of
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-one
and 12.5 ml of tetrahydrofuran were mixed, and cooled down to
-78.degree. C., then, 3.3 ml of a toluene solution (1 mol/l) of
diisobutylaluminum hydride was dropped over a period of 1 hour so
as to keep the temperature at -70.degree. C. or lower.
[0171] After completion of dropping, the mixture was stirred at the
same temperature for 1.5 hours, then, 8.7 ml of water was added and
heated up to 25.degree. C. Further, 5 ml of water and 10 ml of
methyl tert-butyl ether were added, then, the deposited solid was
removed by filtration. The resultant filtrate was
liquid-partitioned, and an aqueous layer was again extracted and
liquid-partitioned using 10 ml of methyl tert-butyl ether. All of
the resultant organic layers were combined and mixed, and magnesium
sulfate was added and mixed, then, solid was removed by filtration.
The resultant filtrate was concentrated under reduced pressure to
distill off the solvent, obtaining 0.48 g of
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol in
the form of white solid. The yield with respect to
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-one
was 94.4%.
Example 4
Synthesis Example of
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol
[0172] 0.20 g (0.89 mmol) of
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-one
and 10 ml of methanol were mixed and cooled down to -10.degree. C.,
then, a solution composed of 0.072 g (3.3 mmol) of lithium
borohydride and 15 ml of tetrahydrofuran was divided into two
portions which were dropped separately at -10.degree. C. The
mixture was stirred for 17 hours at the same temperature, then, 2 g
of water was added, and the mixture was heated up to 25.degree. C.
Further, 15 ml of water and 30 ml of methyl tert-butyl ether were
added and mixed, causing liquid-partitioning. To the resultant
organic layer was added magnesium sulfate and mixed, then, solid
was removed by filtration, to obtain a solution containing 0.16 g
of 3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol
with a yield with respect to
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-one
of 80.1%.
Example 5
Synthesis Example of
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol
[0173] A solution composed of 0.50 g (2.2 mmol) of
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-one
and 5 ml of tetrahydrofuran was dropped into 2.2 ml of a
tetrahydrofuran solution (1 mol/l) of lithium aluminum hydride at
-10.degree. C. over a period of 1 hour, and the mixture was stirred
for 1.5 hours at -10.degree. C. To this solution was added 0.13 g
of water, and further, 0.32 g of a 10% sodium hydroxide aqueous
solution, then, the mixture was heated up to 25.degree. C. Further,
5 ml of water and 10 ml of methyl tert-butyl ether were added,
then, the deposited solid was removed by filtration. The resultant
filtrate was liquid-partitioned, and to an organic layer was added
magnesium sulfate and mixed, then, solid was removed by filtration,
to obtain a solution containing 0.38 g of
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol
with a yield with respect to
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-one
of 77.5%.
Example 6
Synthesis Example of
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carbonitrile
[0174] 1.97 g of a boron trifluoride-diethyl ether complex and 6.2
ml of toluene were mixed and cooled down to -60.degree. C. Into
this mixture, a solution prepared by mixing 5.8 g of a toluene
solution containing 1.45 g (6.4 mmol) of
(1R,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol
obtained by the same manner as in Example 1, 1.37 g of
trimethylsilyl cyanide and 2.5 ml of toluene was dropped over a
period of 3 hours at -60 to -55.degree. C. After completion of
dropping, the mixture was stirred at -60 to -55.degree. C., then,
35 g of an 8% sodium hydrogen carbonate aqueous solution was added,
the mixture was heated up to 25.degree. C., then,
liquid-partitioned. The aqueous layer was again subjected to an
extraction and liquid-partitioning operation using 10 ml of
toluene. The resultant organic layers were combined and mixed, to
this was added magnesium sulfate and mixed, then, solid was removed
by filtration. The resultant solution was partially concentrated
under reduced pressure to distill off the solvent, obtaining 6.68 g
of a solution containing 1.35 g (5.7 mmol) of
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carbonitrile.
[0175] The yield with respect to
(1R,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol
was 89.3%.
[0176] Quantitative determination of
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitri-
le was performed by gas chromatography [column was DB-1, 0.25
mm.phi..times.30 m, 0.25 .mu.m manufactured by J&J].
[0177] The melting point of
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carbonitrile was 45 to 46.degree. C. The .sup.1H-NMR (DMSO-d6)
data of
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carbonitrile are shown below.
[0178] .delta.=5.22 to 4.99 m (1H), 3.43 dd (1H), 3.24 dd (1H),
1.47 to 1.13 m (2H), 1.38 s (9H), 0.96 s (3H), 0.82 s (3H).
Example 7
Synthesis Example of
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carbonitrile
[0179] 7.01 g of a solution containing 1.34 g (5.7 mmol) of
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carbonitrile was obtained in the same manner as in Example 6
excepting that a boron trifluoride-diethyl ether complex and
toluene were mixed and cooled down to -40.degree. C., and into this
mixed liquid, a toluene solution containing
(1R,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol
and trimethylsilyl cyanide was dropped at -45 to -40.degree. C.
over a period of 7 hours.
[0180] The yield with respect to
(1R,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol
was 88.6%.
Example 8
Synthesis Example of
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carbonitrile
[0181] 6.66 g of a solution containing 1.12 g (4.7 mmol) of
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carbonitrile was obtained with a yield with respect to
(1R,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol
of 73.9% in the same manner as in Example 6 excepting that a boron
trifluoride-diethyl ether complex and toluene were mixed and cooled
down to -25.degree. C., and a toluene solution containing
(1R,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol
and trimethylsilyl cyanide was dropped at -25 to -20.degree. C.
over a period of 3 hours.
Example 9
Synthesis Example of
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carbonitrile
[0182] 0.81 g of a boron trifluoride-diethyl ether complex and 11.6
ml of methyl tert-butyl ether were mixed and cooled down to
-40.degree. C. Into this solution, a solution prepared by mixing
2.40 g of a toluene solution containing 0.60 g (2.6 mmol) of
(1R,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol
obtained by the same manner as in Example 1, and 0.53 g of
trimethylsilyl cyanide and 4.6 ml of methyl tert-butyl ether was
dropped at -45 to -35.degree. C. over a period of 3 hours. After
completion of dropping, the mixture was stirred for 4 hours at -45
to -35.degree. C., then, 16 g of an 8% sodium hydrogen carbonate
aqueous solution was added and the mixture was heated up to
25.degree. C., then, liquid-partitioned. The aqueous layer obtained
by liquid-partitioning was again subjected to an extraction and
liquid-partitioning operation using 10 ml of methyl tert-butyl
ether. The resultant organic layers were combined, and to this was
added magnesium sulfate and mixed, then, solid was removed by
filtration. The resultant solution was concentrated under reduced
pressure to distill off a part of the solvent, obtaining 6.06 g of
a solution containing 0.49 g (2.1 mmol) of
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carbonitrile with a yield with respect to
(1R,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol
of 79.2%.
Example 10
Synthesis Example of
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carbonitrile
[0183] 6.04 g of a solution containing 0.47 g (2.0 mmol) of
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carbonitrile was obtained with a yield with respect to
(1R,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol
of 77.7% in the same manner as in Example 9 excepting that methyl
tert-butyl ether used in the reaction was changed to
1-chlorobutane.
Example 11
Synthesis Example of
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carbonitrile
[0184] 6.00 g of a solution containing 0.38 g (1.6 mmol) of
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carbonitrile was obtained in the same manner as in Example 9
excepting that methyl tert-butyl ether used in the reaction was
changed to n-heptane. The yield with respect to
(1R,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol
was 61.5%.
Example 12
Synthesis Example of
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitri-
le
[0185] A solution prepared by mixing 0.20 g (0.88 mmol) of
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol
obtained in the same manner as in Example 3, and 0.19 g of
trimethylsilyl cyanide and 14 ml of methyl tert-butyl ether was
cooled down to -78.degree. C., and 0.27 g of a boron
trifluoride-diethyl ether complex was dropped at -78 to -68.degree.
C. The mixture was thermally insulated at the same temperature for
3 hours, then, heated up to -40.degree. C. and thermally insulated
at the same temperature for 4 hours. To this was added 5.3 g of a
7% sodium hydrogen carbonate aqueous solution, and the mixture was
heated up to 25.degree. C. before liquid-partitioning. The aqueous
layer was further subjected to an extraction and
liquid-partitioning operation twice using 10 ml of methyl
tert-butyl ether. The resultant organic layers were all mixed, and
to this was added sodium sulfate and mixed, then, solid was removed
by filtration. The resultant solution was partially concentrated
under reduced pressure to distill off the solvent, obtaining 0.20 g
of a solution containing 0.17 g (0.73 mmol) of
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitri-
le.
[0186] The yield with respect to
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol
was 83.2%.
[0187] The results of .sup.1H-NMR (CDCl.sub.3) of
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitri-
le are shown below.
[0188] .delta.=4.41 to 4.30 d (1H), 3.63 to 3.54 m (1H), 3.49 to
3.36 m (1H), 1.76 to 1.42 m (2H), 1.49 s (9H), 1.10 s (3H), 0.91 s
(3H).
Example 13
Synthesis Example of
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitri-
le
[0189] 0.27 g of a boron trifluoride-diethyl ether complex and 10
ml of methyl tert-butyl ether were mixed and adjusted to
-40.degree. C. Into this mixed liquid was added 0.18 g of
trimethylsilyl cyanide, then, a solution prepared by mixing 0.77 g
of a toluene solution containing 0.20 g (0.88 mmol) of
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol
obtained in the same manner as in Example 3, and 4 ml of methyl
tert-butyl ether was dropped at -45 to -35.degree. C. After thermal
insulation at the same temperature for 3 hours, 5.3 g of a 7%
sodium hydrogen carbonate aqueous solution was added and the
mixture was heated up to 25.degree. C. before liquid-partitioning.
The aqueous layer was again subjected to an extraction and
liquid-partitioning operation using 20 ml of methyl tert-butyl
ether. The resultant organic layers were all mixed, then, magnesium
sulfate was added and mixed, then, solid was removed by filtration.
The resultant solution was partially concentrated under reduced
pressure to distill off the solvent, obtaining 2.03 g of a solution
containing 0.14 g (0.64 mmol) of
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitri-
le.
[0190] The yield with respect to
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol
was 72.3%.
Example 14
Synthesis Example of
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitri-
le
[0191] A solution prepared by mixing 0.20 g (0.88 mmol) of
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol
obtained in the same manner as in Example 3, and 12 ml of methyl
tert-butyl ether was cooled down to -78.degree. C.
[0192] Into this mixed liquid was added 0.27 g of a boron
trifluoride-diethyl ether complex, then, a solution composed of
0.18 g of trimethylsilyl cyanide and 2 ml of methyl tert-butyl
ether was dropped at -80 to -70.degree. C. After stirring for 4
hours at the same temperature, 5.3 g of a 7% sodium hydrogen
carbonate aqueous solution was added and the mixture was heated up
to 25.degree. C. before liquid-partitioning. The aqueous layer was
again subjected to an extraction and liquid-partitioning operation
using 10 ml of methyl tert-butyl ether. The resultant organic
layers were all mixed, then, sodium sulfate was added and mixed.
Next, solid was removed by filtration. The resultant solution was
partially concentrated under reduced pressure to distill off the
solvent, obtaining 2.17 g of a solution containing 0.10 g (0.52
mmol) of
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitri-
le.
[0193] The yield with respect to
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol
was 59.6%.
Example 15
Synthesis Example of
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carbonitrile
[0194] 1.97 g of a boron trifluoride-diethyl ether complex and 7.5
g of toluene were mixed and cooled down to -40.degree. C. Into this
cooled liquid, a solution prepared by mixing 6.0 g of a toluene
solution containing 1.50 g (6.6 mmol) of
(1R,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol
obtained in the same manner as in Example 1, 1.37 g of
trimethylsilyl cyanide and 2.5 ml of toluene was dropped at
-40.degree. C. over a period of 7 hours, then, the mixture was
thermally insulated at the same temperature for 1 hour. The
resultant solution was dropped at 0 to 10.degree. C. into 7.5 g of
water cooled to 0 to 10.degree. C., then, 3.5 g of a 40% sodium
hydroxide aqueous solution was added, further, an 8% sodium
hypochlorite solution was added, then, the mixture was stirred for
1 hour at room temperature. The residual cyan in the solution was
measured using a test kit for detecting free cyan (KYORITSU
CHEMICAL-CHECK Lab., Corp.: type WAK-CN), to find no residual
cyan.
[0195] To the solution after stirring was added sulfuric acid to
adjust pH to 7 to 8 before performing liquid-partitioning. The
resultant organic layer was washed with 7.5 g of water, to obtain
20.5 g of a solution containing 1.34 g (5.7 mmol) of
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carbonitrile.
[0196] The yield with respect to
(1R,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-ol
was 85.7%.
Example 16
Synthesis Example of methyl
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carboimidate and methyl
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carboxylate
[0197] 56.0 g of a solution containing 36.5 g (154 mmol) of
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carbonitrile obtained in the same manner as in Example 9, and 349
g of methanol and 53.4 g of potassium carbonate were mixed, then,
cooled down to 0.degree. C., and stirred for 9 hours at 0.degree.
C.
[0198] A solution containing 40.0 g (149 mmol) of methyl
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carboimidate was obtained.
[0199] The yield with respect to
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carbonitrile was 96.5%.
[0200] Into a solution containing 40.0 g (149 mmol) of methyl
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carboimidate described above, 491 g of 7% hydrochloric acid was
dropped at 0.degree. C. over a period of 1 hour, then, the mixture
was stirred at 0.degree. C. for 8 hours, then, concentrated under
reduced pressure to distill off the solvent, then, 182 g of methyl
tert-butyl ether was added to cause liquid-partitioning. The
aqueous layer was again subjected to an extraction and
liquid-partitioning operation using 182 g of methyl tert-butyl
ether. The resultant organic layers were all mixed, then, 109 g of
water was added and mixed to cause liquid-partitioning. The
resultant organic layer was concentrated under reduced pressure to
distill off the solvent, then, 109 g of toluene was further added,
then, concentrated under reduced pressure to distill off the
solvent, obtaining 75.0 g of a solution containing 40.6 g (151 mol)
of methyl
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carboxylate.
[0201] The yield with respect to
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carbonitrile was 97.3%.
Example 17
Synthesis Example of ethyl
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylat-
e
[0202] 1.35 g of a solution containing 1.00 g (4.2 mmol) of
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitri-
le, and 25 ml of ethanol and 1.46 g of potassium carbonate were
stirred at 20 to 30.degree. C. for 70 hours, then, 13.5 g of 7%
hydrochloric acid was dropped at 20 to 30.degree. C., then, the
mixture was stirred for 3 hours. By concentration under reduced
pressure, the solvent was distilled off, then, 10 ml of methyl
tert-butyl ether and 10 ml of water were added and mixed before
liquid-partitioning. Next, an operation of extraction of an aqueous
layer with 10 ml of methyl tert-butyl ether and liquid-partitioning
thereof was repeated twice. The resultant organic layers were all
mixed, then, sodium sulfate was added into this organic layer and
mixed, then, solid was removed by filtration. The resultant
solution was concentrated under reduced pressure to distill off the
solvent, obtaining a solution containing 1.38 g of ethyl
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylat-
e. In this solution, about 10% of
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitri-
le as a raw material compound remained.
[0203] Into the resultant solution, 25 ml of ethanol and 1.46 g of
potassium carbonate were again added, and the mixture was stirred
at 20 to 30.degree. C. for 17 hours, then, 13.5 g of 7%
hydrochloric acid was dropped at 20 to 30.degree. C., then, the
mixture was stirred for 2 hours. By concentration under reduced
pressure, the solvent was distilled off, then, 10 ml of methyl
tert-butyl ether and 10 ml of water were added and mixed before
liquid-partitioning. Further, an aqueous layer extraction and
liquid-partitioning operation was carried out twice using 10 ml of
methyl tert-butyl ether. The resultant organic layers were all
mixed, then, into this organic layer was added sodium sulfate and
mixed. Next, solid was filtrated, then, the resultant filtrate was
concentrated under reduced pressure to distill off the solvent.
After distillation, 1.34 g of a solution containing 1.18 g (4.2
mmol) of ethyl
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylat-
e was obtained.
[0204] The yield of
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic
acid ethyl ester with respect to
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonitri-
le was 98.6%.
Example 18
Synthesis Example of methyl
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carboimidate
[0205] 1.42 g of a solution containing 1.00 g (4.23 mmol) of
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carbonitrile obtained in the same manner as in Example 9, and 5.0
g of methanol and 1.47 g of potassium carbonate were mixed and
cooled down to 0.degree. C., and stirred for 20 hours at 0.degree.
C. To this solution was added 5.0 g of water and 5.0 g of toluene
at 0.degree. C. and a liquid-partitioning operation was performed.
The aqueous layer was again subjected to an extraction and
liquid-partitioning operation using 2.5 g of toluene. The resultant
organic layers were all mixed, and the solvent was distilled off by
concentration under reduced pressure, obtaining 1.15 g of an oily
substance containing 1.06 g (3.95 mol) of
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carboimidate. The yield of methyl
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carboimidate with respect to
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carbonitrile was 93.4%.
[0206] The results of .sup.1H-NMR (CDCl.sub.3) of methyl
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carboimidate are shown below.
[0207] .delta.=4.14 to 4.01 d (1H), 3.81 s (3H), 3.64 to 3.43 m
(2H), 1.51 to 1.28 m (2H), 1.39 (9H), 1.03 s (3H), 0.93 s (3H).
Example 19
Synthesis Example of methyl
(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate
hydrochloride
[0208] Into a solution prepared by dissolving 1.80 kg of a hydrogen
chloride gas in 6.82 kg of methanol, 9.13 kg of a toluene solution
containing 6.68 kg (24.8 mol) of methyl
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carboxylate obtained in the same manner as in Example 16 was
dropped at 25 to 30.degree. C. over a period of 3 hours, and 4.2 kg
of toluene was added and the mixture was stirred at 25 to
30.degree. C. for 4 hours. 28.0 kg of methyl tert-butyl ether was
added, and a seed crystal of methyl
(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate
hydrochloride was added at 30.degree. C. Subsequently, 78.7 kg of
methyl tert-butyl ether was dropped over a period of 2 hours, then,
the mixture was cooled down to -5.degree. C. over a period of 11
hours, and stirred at -5.degree. C. for 3 hours. The deposited
crystal was filtrated, then, washing with 13.3 kg of methyl
tert-butyl ether was carried out three times. 4.94 kg of the
resultant crystal was dried under reduced pressure, obtaining 4.47
kg (21.7 mol) of a crystal containing methyl
(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate
hydrochloride.
[0209] The yield of methyl
(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate
hydrochloride with respect to methyl
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carboxylate was 91.0%.
[0210] Next, 79.6 g of the resultant crystal [containing 72.0 g of
methyl
(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate
hydrochloride] and 274 g of 2-propanol were mixed and heated up to
45 to 50.degree. C. to dissolve the crystal. To this solution was
added a seed crystal of methyl
(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate
hydrochloride at 38.degree. C. After stirring for 30 minutes at
38.degree. C., the mixture was cooled down to -5.degree. C. over a
period of 9 hours. After stirring at -5.degree. C. for 1 hour, 274
g of methyl tert-butyl ether was dropped over a period of 3 hours,
and further, the mixture was thermally insulated at -5.degree. C.
The deposited crystal was filtrated, then, washed twice with a
solution composed of 36 g of 2-propanol and 36 g of methyl
tert-butyl ether, and further washed using 72 g of methyl
tert-butyl ether. The resultant crystal was dried under reduced
pressure, obtaining 64.2 g of a crystal of methyl
(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate
hydrochloride with a yield in the re-crystallization operation of
89.2%.
[0211] The overall yield from methyl
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carboxylate was 81.2%.
Example 20
Synthesis Example of methyl
(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate
hydrochloride
[0212] Into 173 g of a methanol solution containing 20 wt % of
hydrogen chloride, a solution prepared by mixing 152 g of a toluene
solution containing 86.3 g (321 mmol) of methyl
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carboxylate obtained in the same manner as in Example 16, and 12.0
g of toluene was dropped at 20.degree. C. 8.6 g of toluene was
added and the mixture was stirred at 20.degree. C. for 5 hours. To
this solution was added 1036 g of methyl tert-butyl ether, then, a
seed crystal of methyl
(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate
hydrochloride was added, and further, 690 g of methyl tert-butyl
ether was dropped over a period of 1 hour. The resultant mixed
liquid was cooled down to 0.degree. C. over a period of 2 hours.
After stirring for 2 hours at 0.degree. C., the deposited crystal
was filtrated, then, washed using 210 g of methyl tert-butyl ether.
The resultant crystal was dried under reduced pressure to obtain
53.8 g of a crystal of methyl
(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate
hydrochloride.
[0213] The yield of methyl
(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate
hydrochloride with respect to methyl
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carboxylate was 81.6%.
Example 21
Synthesis Example of methyl
6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate
hydrochloride
[0214] 0.32 g (1.2 mmol) of methyl
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylat-
e, and 1.16 g of an ethyl acetate solution containing 15 wt % of
hydrogen chloride were mixed at 25.degree. C., then, thermally
insulated at 25.degree. C.
[0215] Disappearance of methyl
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylat-
e was confirmed, then, the reaction liquid was concentrated under
reduced pressure to distill off the solvent. To the resultant
concentration residue was added 0.32 g of toluene and 0.5 ml of
methanol, and the mixture was heated up to 40.degree. C. to
dissolve the deposited crystal. Into the resultant solution, 1.6 ml
of methyl tert-butyl ether was dropped. A slurry containing the
deposited crystal was cooled down to 0.degree. C. The slurry liquid
was filtrated to obtain a crystal which was then washed using
methyl tert-butyl ether. The resultant crystal was dried under
reduced pressure, to obtain 0.11 g (0.53 mmol) of methyl
6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate
hydrochloride.
[0216] The yield of methyl
6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride
was 44.9% with respect to methyl
3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylat-
e.
Example 22
Synthesis Example of methyl
(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate
hydrochloride
[0217] 1.00 g (4.23 mmol) of
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carbonitrile, and 7.00 g of a methanol solution containing 20 wt %
of hydrogen chloride were mixed at 20.degree. C. to 30.degree. C.,
then, thermally insulated at the same temperature. Disappearance of
the raw material compounds was confirmed, then, the reaction liquid
was concentrated under reduced pressure to distill off the solvent,
to obtain 1.06 g of an oily substance containing 0.55 g (2.67 mmol)
of methyl
(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate
hydrochloride.
[0218] The yield of methyl
(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate
hydrochloride with respect to
(1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
-carbonitrile was 63.1%.
INDUSTRIAL APPLICABILITY
[0219] The proline derivative obtained by the production method of
the present invention is useful as a chemical raw material and
medical-agricultural drug intermediate.
* * * * *